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X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development.

Original publication

DOI

10.1016/j.devcel.2012.06.011

Type

Journal article

Journal

Dev Cell

Publication Date

14/08/2012

Volume

23

Pages

265 - 279

Keywords

Alleles, Animals, Cell Line, Chromosomal Proteins, Non-Histone, CpG Islands, DNA Methylation, Mice, Protein Isoforms, X Chromosome Inactivation